The Role of Signal Transducer and Activator of Transcription 1 (STAT1) and 3 (STAT3) in Primary and Metastatic Breast Cancer

Breast cancer is the most frequently diagnosed malignancy and the second most lethal cancer in women. Metastasis in breast cancer is invariably responsible for patient death and is comprised of many steps, of which proliferation in vital organs is responsible for morbidity and mortality due to vital organ failure. Patients with the metastatic disease are limited to chemotherapy, which non-specifically targets proliferating cells. Despite it being initially effective, chemotherapy is associated with high toxicity and many patients develop resistance. Thus, there is an urgent need to characterize the biology of metastatic breast cancer to develop targeted therapies for the late-stage disease. EGFR is a member of the ErbB family of receptor tyrosine kinases, which have particular relevance in breast tumorigenesis. Clinical studies show that high expression levels of EGFR in the primary mammary tumors correlate with poor prognosis and decreased survival of breast cancer patients due to metastasis. Patient data is supported by experimental and pre-clinical studies, which describe various signaling pathways that mediate the oncogenic effects of EGFR, such as the MAPK, STAT3, and PI3K pathways. Despite these well-documented roles of EGFR, clinical trials evaluating EGFR inhibitors (EGFRi) in metastatic breast cancer have been unanimously unsuccessful in improving patient prognosis, and the mechanisms that contribute to this intrinsic resistance are unknown. To characterize the signaling events that govern EGFR behavior in metastatic breast cancer resistant to EGFRi, we utilized multiple pre-clinical breast cancer progression series and patient-derived cells that display the intrinsic resistance phenomenon. In these models, EGFR functions as a pro-apoptotic molecule whose ligand-mediated activation results in growth inhibition and/or apoptosis of metastatic breast cancer cells. Here we show that in the later stages of metastasis, increased nuclear translocation of EGFR leads to increased physical access to STAT1 and ...